July 7, 2020 - COVID-19, FDA, United States

FDA Establishes Clear Requirements for COVID-19 Vaccine

On June 30, 2020, the U.S. Food and Drug Administration released its much anticipated guidance on the licensure of COVID-19 (SARS-CoV-2) vaccines. According to the New York Times, there are currently over 145 COVID-19 vaccines in development across the globe with 20 in human trials. There are several different types of COVID-19 vaccines in development, including genetic vaccines (based on RNA/DNA fragments from the coronavirus to provide an immune response), viral vector vaccines (inserting coronavirus genes using an adenovirus), protein-based vaccines (using a protein fragment from the coronavirus as the antigen to produce an immune response), and whole virus vaccines (using attenuated virus).

To support COVID-19 vaccine development efforts, the U.S. Government launched Operation Warp Speed (OWS) in May 2020 with the goal of having substantial quantities of a safe and effective vaccine available for Americans by January 2021, through government assistance to accelerate development, manufacturing, and distribution of a COVID-19 vaccine. Under the OWS program, Congress has designated over $6.5 billion for countermeasure development through the Biomedical Advanced Research and Development Authority (BARDA), along with $3 billion for National Institutes of Health (NIH) research. On June 16th, the HHS announced that the OWS program has reportedly narrowed down its list from 14 vaccine candidates to about seven candidates. Thus far, the OWS program has awarded the following grants for vaccine development: (i) $456 million to Johnson & Johnson’s candidate vaccine, with Phase 1 clinical trials set to begin this summer; (ii) up to $483 million to Moderna’s candidate vaccine, which received a fast-track designation from the FDA, expecting to start Phase 3 clinical testing in July 2020; and (iii) up to $1.2 billion to AstraZeneca’s candidate vaccine being co-developed with the University of Oxford with an agreement to make available at least 300 million doses of the vaccine for the United States, with the first doses delivered as early as October 2020 and Phase 3 clinical testing beginning this summer with approximately 30,000 volunteers in the United States.

The FDA’s recent COVID-19 vaccine guidance describes current recommendations regarding the data needed to facilitate clinical development and licensure of vaccines to prevent COVID-19. Specifically, the FDA provided key considerations for (i) Chemistry, Manufacturing, and Controls (CMC), (ii) nonclinical data, (iii) clinical trials, (iv) post-licensure safety evaluation, (v) diagnostic and serological assays, and (vi) additional considerations. The FDA did not create a special accelerated pathway or designation for COVID-19 vaccines – the usual FDA Biologics License Application (BLA) framework rules still apply including Fast Track designation. However, the FDA is still willing to accept an Emergency Use Application (EUA) for a COVID-19 vaccine, but would effectively require the same safety and efficacy clinical data along with quality and purity manufacturing data as a BLA. In the guidance, the FDA explicitly stated that “for a vaccine for which there is adequate manufacturing information, issuance of a EUA may be appropriate once studies have demonstrated the safety and effectiveness of the vaccine but before the manufacturer has submitted and/or FDA has completed its formal review of the biologics license application.” Moreover, the FDA clarified that all current good laboratory, clinical, and manufacturing practices fully apply throughout the vaccine development process.

The FDA has made it clear that there are no surrogate endpoints that can reasonably predict the clinical benefit of a COVID-19 vaccine, and thus, vaccine developers should pursue traditional approval via direct evidence of vaccine safety and efficacy in protecting humans from SARS-CoV-2 infection and/or clinical disease. The FDA requires that the primary efficacy endpoint estimate for a placebo-controlled efficacy trial should be at least 50% based on scientifically acceptable biostatistics standards set forth in the FDA guidance. For reference, in December 2019, the FDA approved the live Ebola vaccine, Ervebo, which demonstrated a point estimate of vaccine efficacy of 100% (95% CI: 63.5% to 100%) in 3,537 subjects ≥ 18 years of age. On the other hand, during the 2019-2020 flu season, the influenza vaccine efficacy rate was 22-45% depending on the virus strain and age group demographics. The scientific challenge in developing a first generation vaccine in the midst of a global pandemic is striking the right balance between maximizing efficacy while reducing safety concerns from immunological or inflammatory side effects. The 50% minimum efficacy threshold may represent the FDA’s position that it will tolerate lower efficacy, while requiring greater safety given the prevalence of COVID-19 in the United States. 

From a safety perspective, vaccine developers are advised to collect and evaluate at least preliminary clinical safety and immunogenicity data for each dose level and age group (e.g., younger versus older adults) to support progression of clinical development to include larger numbers (e.g., hundreds) of participants and participants at higher risk of severe COVID-19. Based on the recent guidance, the FDA requires two specific sets of safety data in addition to standard requirements of immunogenicity and other safety studies. The first data set consists of studies to address the risk for vaccine-associated enhanced respiratory disease (ERD). Specifically, the FDA has recommended the use of predictive animal models to assess the likelihood of ERD, including post-vaccination challenge studies where the animal is introduced to the COVID-19 virus after receiving the vaccine to correlate how viral exposure might affect humans after receiving the vaccine, along with non-clinical studies evaluating protection and/or histopathological markers of vaccine-associated ERD following SARS-CoV-2 challenge. The second set of preliminary data that the FDA has requested include assessments of neutralizing vs. total antibody responses along with polarization data of T-helper cells types 1 and 2 to better understand the type and patterns of immune response that SARS-CoV-2 induces.

Another key issue with developing, scaling, and marketing a COVID-19 vaccine is quality, purity, and stability of the vaccine product during the manufacturing and distribution process. The FDA is encouraging leveraging established and validated vaccine development platforms, which benefits the pharmaceutical companies that have previously developed and commercialized a vaccine. First-time vaccine developers should work closely with their contract manufacturers or consider collaborating with other organizations that have a validated vaccine manufacturing infrastructure. Vaccine developers are also advised and encouraged to communicate early with the Office of Vaccines Research and Review (OVRR) to discuss the type and extent of CMC information needed for development and licensure of their COVID-19 vaccine. Details of the manufacturing process must be provided in a BLA to market a COVID-19 vaccine. Accordingly, vaccine developers should submit data and information identifying critical process parameters, critical quality attributes, batch records, defined hold times, and the in-process testing scheme, along with establishing specifications for each critical parameter. Validation data from the manufacture of platform-related products may provide useful supportive information, particularly in the identification of critical parameters. Prior to approving the BLA, the FDA typically performs an onsite inspection of manufacturing facilities. However, in view of the COVID-19 pandemic, the FDA stated that it will use “additional tools, where available, to determine the need for an on-site inspection and to support the application assessment, such as reviewing a firm’s previous compliance history, and requesting records in advance of or in lieu of on-site inspections or voluntarily from facilities and sites.” Thus, vaccine developers should also anticipate additional documentation requests from the FDA in lieu of the on-site inspection.


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